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      CCL2 Disrupts the Adherens Junction: Implications for Neuroinflammation

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          Abstract

          Alterations to blood-brain barrier (BBB) adhesion molecules and junctional integrity during neuroinflammation can promote central nervous system (CNS) pathology. The chemokine CCL2 is elevated during CNS inflammation and is associated with endothelial dysfunction. The effects of CCL2 on endothelial adherens junctions (AJ) have not been defined. We demonstrate that CCL2 transiently induces Src-dependent disruption of human brain microvascular endothelial AJ. β-catenin is phosphorylated and traffics from the AJ to PECAM-1, where it is sequestered at the membrane. PECAM-1 is also tyrosine phosphorylated, an event associated with recruitment of the phosphatase SHP-2 to PECAM-1, β-catenin release from PECAM-1, and reassociation of β-catenin with the AJ. Surface localization of PECAM-1 is increased in response to CCL2. This may enable the endothelium to sustain CCL2-induced alterations in AJ and facilitate recruitment of leukocytes into the CNS. Our novel findings provide a mechanism for CCL2-mediated disruption of endothelial junctions that may contribute to BBB dysfunction and increased leukocyte recruitment in neuroinflammatory diseases.

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          Multiple sclerosis--the plaque and its pathogenesis.

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            Protein regulation by monoubiquitin.

             L Hicke (2001)
            Multi-ubiquitin chains at least four subunits long are required for efficient recognition and degradation of ubiquitylated proteins by the proteasome, but other functions of ubiquitin have been discovered that do not involve the proteasome. Some proteins are modified by a single ubiquitin or short ubiquitin chains. Instead of sending proteins to their death through the proteasome, monoubiquitylation regulates processes that range from membrane transport to transcriptional regulation.
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              Tyrosine phosphorylation of focal adhesion kinase at sites in the catalytic domain regulates kinase activity: a role for Src family kinases.

              Focal adhesion kinase (FAK) is a widely expressed nonreceptor protein-tyrosine kinase implicated in integrin-mediated signal transduction pathways and in the process of oncogenic transformation by v-Src. Elevation of FAK's phosphotyrosine content, following both cell adhesion to extracellular matrix substrata and cell transformation by Rous sarcoma virus, correlates directly with an increased kinase activity. To help elucidate the role of FAK phosphorylation in signal transduction events, we used a tryptic phosphopeptide mapping approach to identify tyrosine sites of phosphorylation responsive to both cell adhesion and Src transformation. We have identified four tyrosines, 397, 407, 576, and 577, which are phosphorylated in mouse BALB/3T3 fibroblasts in an adhesion-dependent manner. Tyrosine 397 has been previously recognized as the major site of FAK autophosphorylation. Phosphorylation of tyrosines 407, 576, and 577, which are previously unrecognized sites, is significantly elevated in the presence of c-Src in vitro and v-Src in vivo. Tyrosines 576 and 577 lie within catalytic subdomain VIII--a region recognized as a target for phosphorylation-mediated regulation of protein kinase activity. We found that maximal kinase activity of FAK immune complexes requires phosphorylation of both tyrosines 576 and 577. Our results indicate that phosphorylation of FAK by Src (or other Src family kinases) is an important step in the formation of an active signaling complex.
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                Author and article information

                Journal
                0376617
                5462
                Lab Invest
                Lab. Invest.
                Laboratory investigation; a journal of technical methods and pathology
                0023-6837
                1530-0307
                12 April 2012
                28 May 2012
                August 2012
                01 February 2013
                : 92
                : 8
                : 1213-1233
                Affiliations
                [1 ]The Albert Einstein College of Medicine, Department of Pathology, Bronx, NY
                [2 ]Department of Microbiology and Immunology, Bronx, NY
                [3 ]Public Health Institute of Research (PHRI) and Department of Microbiology and Molecular Genetics, UMDNJ, Newark, NJ
                [4 ]The Open University, Department of Biological Sciences, Milton Keynes, UK
                [5 ]Division of Hematology and Medical Oncology, Weill Medical College of Cornell University, New York, NY
                [6 ]Institut Cochin, Department de Biologie Cellulaire, Université René Descartes, Paris, France
                Author notes
                [* ]Correspondence to: Dr. Joan W. Berman, Department of Pathology, F727, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY, 10461, USA. Telephone: 718-430-3194; FAX: 718-430-8541. joan.berman@ 123456einstein.yu.edu
                Article
                NIHMS363511
                10.1038/labinvest.2012.80
                3409314
                22641100

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                Categories
                Article

                Pathology

                ve-cadherin, β-catenin, pecam-1, cd31, mcp-1, endothelial cells, neuroinflammation

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